A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

GOLPH3 Regulates EGFR in T98G Glioblastoma Cells by Modulating Its Glycosylation and Ubiquitylation

Protein trafficking is altered when normal cells acquire a tumor phenotype. A key subcellular compartment in regulating protein trafficking is the Golgi apparatus, but its role in carcinogenesis is still not well defined. Golgi phosphoprotein 3 (GOLPH3), a peripheral membrane protein mostly localized at the trans-Golgi network, is overexpressed in several tumor types including glioblastoma multiforme (GBM), the most lethal primary brain tumor. Moreover, GOLPH3 is currently considered an oncoprotein, however its precise function in GBM is not fully understood. Here, we analyzed in T98G cells of GBM, which express high levels of epidermal growth factor receptor (EGFR), the effect of stable RNAi-mediated knockdown of GOLPH3. We found that silencing GOLPH3 caused a significant reduction in the proliferation of T98G cells and an unexpected increase in total EGFR levels, even at the cell surface, which was however less prone to ligand-induced autophosphorylation. Furthermore, silencing GOLPH3 decreased EGFR sialylation and fucosylation, which correlated with delayed ligand-induced EGFR downregulation and its accumulation at endo-lysosomal compartments. Finally, we found that EGF failed at promoting EGFR ubiquitylation when the levels of GOLPH3 were reduced. Altogether, our results show that GOLPH3 in T98G cells regulates the endocytic trafficking and activation of EGFR likely by affecting its extent of glycosylation and ubiquitylation.     

Hierarchical micro-nanostructured albite-based glass-ceramic for high dielectric strength insulators

A novel glass-ceramic material based on albite type Na-rich feldspar has been synthesized by conventional ceramic process. High crystallinity, >94%?Vol.% is obtained by fast sintering which allows energy saving processing. Albite is the main crystalline phase and tetragonal SiO₂ is a secondary phase. Electrical properties were examined by complex impedance, DC measurements, and dielectric breakdown test. Dielectric characterization shows a non-Debye type dielectric behavior with low dielectric constant, 4.6 at 1?MHz, low dielectric losses, (～10^?3 at 1?MHz, and a large dielectric strength, ～60?kV/mm), that it is the largest value reported in ceramic insulators. Those dielectric properties are attained by the low glassy phase content in the samples and their unique micro-nanostructure. All these properties make this novel material a very promising candidate in the market of ceramic electrical insulator, highlighting for high-voltage applications.     

An assessment of the Spanish national hydrological plan

The paper is a comprehensive review of the Spanish National Hydrological Plan, which proposes to transfer water from the lower part of the Ebro River up to the Levante basins, around 912 km away. The National Hydrological Plan is a conventional, static plan, which focuses primarily on supply management. The plan is based on the explicit assumption that the world will change only incrementally during its entire economic life of 100-200 years. The analysis indicates that much of the increased water demands forecasted are unlikely to materialize due to increasing emphasis on demand management practices, major structural changes in the agricultural sector that will occur by 2020 and the requirements of the Water Directive of the European Union, which must be fulfilled by 2010. Even now, the cost per cubic metre of water delivered at the end of the transfer is nearly twice the cost of desalinated water. The National Hydrological Plan in its present form cannot be justified for economic, environmental and social reasons. In addition, the plan will not be necessary if demand management practices are implemented.     

Intra- and inter-laboratory reproducibility of estrogen and progesterone receptor enzyme immunoassay in breast cancer cytosol samples--a Swedish multicenter study. Swedish Society of Cancer Study Group

Estrogen and progesterone receptor analysis results were compared within and between six laboratories in Sweden using frozen breast cancer cytosol samples, and the same technique (enzyme immunoassay, Abbott Laboratories). The concordance in receptor status (positive vs. negative) was excellent (98.4% (571/580)). The discordant results were attributable to values near cut-off (n = 4) or outliers (n = 5), the latter probably being due to analytical errors. One laboratory reported significantly higher ER concentrations than the others; thus caution should be observed when comparing absolute values from different centers. For PgR there were similar differences between the laboratories. However, the intra- and inter-laboratory differences were small compared with the overall variability in ER and PgR content between different samples in a large database. The range of the median intra-laboratory coefficient of variation was 11-23% for ER and 12-19% for PgR, indicating that there is room for improvement in the quality of assay performance.     

Generation of Technology-Independent Retargetable Analog Blocks

This paper introduces a complete methodology for retargeting of analog cells to different sets of specifications. This methodology is technology-independent, thus allowing the migration, from one technology to another, of the circuit under retargeting. Careful integration of the device sizing and layout generation tasks via the incorporation of layout constraints during the sizing process allows to generate fully functional designs in a few minutes. The methodology is illustrated via the retargeting of a fully-differential Miller-compensated two-stage operational amplifier for a new set of specifications and two different technological processes.An erratum to this article can be found at